1 Introduction

Bone tumours accounted for about 1 % of all cancers in population-based registries, with Ewing sarcoma of the bone accounting for 15.5 % of all bone cancers.^1–3 In 1921, J. Ewing first identified this disease as diffuse endotheliomas of the bone that were radiosensitive and distinct from osteogenic sarcomas or giant cell tumours.³

Ewing's sarcoma is highly aggressive disease usually affecting bones having predilection for younger age groups. More than 90 % of Ewings sarcoma family tumour malignancies have the t^11,22 translocation, which recombines the FLI-1 and EWS genes on chromosome 22 and these recombinations result in abnormal proteins, which are thought to lead to improper DNA transcription and an ESFT malignancy.³

Most of the Ewings sarcoma patients have micro metastasis at presentation and requires a systemic control alongside loco-regional treatment.^1–7 Due to its proliferative nature, management consist neoadjuvant chemotherapy followed by surgical treatment or definitive radiotherapy and adjuvant chemotherapy treatment.^3–7 Patients can be treated with neoadjuvant chemotherapy followed by definitive radiotherapy and adjuvant chemotherapy with good oncological outcomes(Fig. 1).

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Fig. 1 Ewings Sarcoma of Ulna bone treated with Definitive radiotherapy treatment with four year follow-up.

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The common locations for affection of Ewing's sarcoma are femur, tibia and pelvis and it rarely involves bones of upper extremity. In current medical literature very few studies considered into account demographic pattern, clinical nature and survival outcome of Ewings sarcoma of extremities. The review of literature suggests limited data available on outcomes of Ewing's sarcoma affecting various location in the skeletal system.^1–8 The outcome of Ewing's sarcoma of upper limb need to be evaluated in detail as its prognosis as may be different compared to other sites. Simpson et al. had published a data on upper extremity Ewing's sarcoma with limited number of cases.⁸

The aim and objectives of current study were to examine to clinico-radiological, functional and oncological outcomes of patients with Ewing's sarcoma of upper extremity treated at a tertiary cancer centre.

2 Materials and methods

From 2015 to 2022, 45 patients of upper extremity Ewing's sarcoma who treatment at a tertiary cancer care centre(Fig. 2). Out of which 26 patients of upper extremity Ewing's sarcoma underwent surgical management. Patients from all age groups which were non metastatic at presentation were included.

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Fig. 2 Flow chart of selection of patients with Ewings sarcoma of Upper Limb in current study.

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Patients from all age groups which were non metastatic at presentation were included.

As per our institute protocol, each patient underwent local part imaging with a plain radiograph by MRI followed by IITV guided or direct J needle biopsy was carried out after imaging (Figs. 3 and 4). Metastatic workup was performed with CT thorax and Bone scan and Bone marrow biopsy or with PET scan for indeterminate lesions (Fig. 5). Patients were treated with neoadjuvant chemotherapy after Immuno-histo chemistry(IHC) confirmed Ewing's sarcoma as diagnosis. Vincristine, Doxorubicin, Cyclophosphamide, Ifosfamide, Etoposide, and Actinomycin were the six chemotherapy medicines used in the high risk protocol, which was the usual treatment for all patients.

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Fig. 3 Radiograph of shoulder with anteroposterior view showing lytic lesion affecting scapula.

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Fig. 4 Magnetic resonance imaging of shoulder joint axial section showing involvement of scapula and rotator cuff muscles.

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Fig. 5 Positron emission tomography showing increased uptake of FDG around scapula.

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For a period of 12 weeks prior to surgery, all patients received the VACM protocol as part of their treatment plan, which consists of a four-drug regimen consisting of vincristine, doxorubicin, cyclophosphamide,ifosfamide, etoposide and mesna.⁸ The dosage of vincristine(2mg/m2, iv push),doxorubicin (37.5mg/m2 for 2 days i/v over 30 min),cyclophosphamide (600 mg/m2 for 2 days i/v over 1 h),ifosfamide1.8 gm/m2 for 5 days iv over 1 h),etoposide(100mg/m2 for 5 days,i/v over 1 h) and Mesna (360 mg/m2 at 1,4,8 h after cyclophosphamide or ifosfamide.

Patients were sent for a surgical evaluation after 12 weeks of chemotherapy and a total of 48 weeks of chemotherapy was given to them.

After neoadjuvant chemotherapy was finished, magnetic resonance imaging, CT-thorax was done to re-stage the disease followed by which index surgery was performed. Surgical planning was done after a multi-disciplinary tumour board discussion with medical oncologist and radiation oncologist. Surgical treatment was performed following counselling, written and informed consent from the patient and their relatives.

Adjuvant chemotherapy was administered following surgical management. Regular follow-up of the patients by clinical evaluation, radiograph of affected extremity,CT thorax and Bone scan every 3 monthly till first three years and followed by 6 months for next two years. From the institute's prospectively maintained database, we gathered information on the clinical course, treatment, radiological and histological characteristics, and demographics of all 26 patients affected by Ewings sarcoma of upper extremity. Each case was followed up till its last visit at the hospital from our registry. Any recurrence was recorded and looked into further using confirmation from a biopsy.

Statistical analysis for Overall Survival (OS) and Disease Free Survival (DFS) was done using Kaplan–Meier curve analysis with SPSS software for data analysis.

Prior written informed consent was obtained from all patients for future use of their data in accordance with institute protocol, and the study was authorised by the hospital's clinical ethics committee.

3 Results

3.2

3.2 Post neoadjuvant chemotherapy data

Surgeries were planned according to response to neoadjuvant chemotherapy. Out of 26 cases, 19 cases (73 %) underwent limb salvage surgeries including Scapulectomy, wide local excision for ulna lesion, wide local excision and fixation, wide local excision and ulna centralization for radius lesion, wide excision with megaprosthesis or a wide excision with ECRT and fixation. Amputation was performed in 7 patients (27 %) of which ray resection in one case and forequarter amputation was performed in six cases. In one patient underwent Scapulectomy had axillary artery injury for which end to end anastomosis of vessel was performed.This patient developed lung metastasis after 3 years.

3D printed scapula was placed in three patients following scapulectomy surgery(Fig. 6). The surgical planning for 3D printed implant was done with MRI, CT scan of chest, computed aided design (CAD) followed by printing of a titanium implant (Figs. 4 and 5).

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Fig. 6 Intra-Operative image (A) clinical photograph showing posterior approach for scapula. (B)- showing Neuro-vascular bundle(NV) post scapulectomy and Humeral head(H) (C)-showing margins of surrounding muscle after scapulectomy.

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In cases with 3D printed scapula showing reconstruction of shoulder joint: scapula and humerus was performed using non-absorbable prolene mesh and acromio-clavicular joint reconstruction with help of k-wires and non absorbable suture materials (Figs. 7 and 8). The patient had limitation of shoulder movement as compared to opposite side and post-operative radiograph at 1 year follow-up(Fig. 9).

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Fig. 7 Intra-Operative image (A) showing dissection of muscle with the help of vessel sealing devices. (B) showing specimen of resected scapula with wide margin and the tumor well covered by muscles. (C) showing reconstruction of scapula using patient specific 3D-printed scapula.

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Fig. 8 Intra-Operative image (A) showing reconstruction of shoulder joint using non-absorbable prolene mesh and acromio-clavicular joint reconstruction with help of k-wires. (B) showing coverage of scapula with help of surrounding muscles.

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Fig. 9 Post-operative image (A) showing clinical photograph after 3D-scapula reconstruction with healed surgical scar around left shoulder. (B) Post-operative radiograph at 1 year follow-up of shoulder joint-anteroposterior and lateral view showing 3D-printed scapula with neo-shoulder joint.

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Another patient with lesion in shaft of humerus treated with ECRT and plate fixation had plate exposure after 3 years in which plate removal was performed. Six cases of proximal humerus lesions underwent forequarter amputation. These cases had following chemotherapy had encasement of neurovascular bundle and limb salvage was not feasible.

3.3

3.3 Oncologic data

Out of 26, 13 (50 %) patients developed metastasis on follow up. Out of 13 patients with metastasis, 8 developed lung metastasis on follow up, 3 had brain metastasis and 2 had bone metastasis (Table 2).

Table 2 Oncological data of patients of upper limb Ewing's sarcoma.

Features	Outcome
Pathological Fracture
No	24 (92.3 %)
Yes	2 (7.7 %)
Metastasis
No	13 (50 %)
Yes	13 (50 %)
Lung metastasis	8
Brain metastasis	3
Skeletal metastasis	2
Mean tumour necrosis	68 %
Event free survival
Minimum	0.5 m
Maximum	77 m
Mean	23.05 m

In one case with radius ewings sarcoma treated with wide local excision developed isolated single lung metastasis on second and third year of presentation was managed with thoracoscopic metastatectomy and remains disease free at present. Rest of the patients were referred for palliative radiotherapy for lung or brain metastasis.

The Event free survival (EFS) in current study was 70 % at 12 months and 40 % at 24 months (Fig. 10). Mean Event free survival (EFS) in current study was 33.5 months (22.3–44.6) and Median Event free survival (EFS) in current study was 25 months (19.7–30.2).

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Fig. 10 Event free survival rate in patients in Ewings sarcoma of upper limb treated with surgical management.

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4 Discussion

Ewing sarcoma (ES) is second most common primary malignant bone tumor in children and adolescents following osteosarcoma with an annual incidence of one to three persons per million and a peak incidence in the second decade of life.⁹ The majority of Ewing sarcomas affects osseous skeleton, while only 2.8 % of cases had extra-skeletal Ewing sarcomas.^11,12 The most common location of Ewings sarcoma is diaphyseal region of long and flat bones.

Majority of the studies published data have discussed about clinico-oncological outcomes of Ewings sarcoma of lower extremity and chest wall tumours whereas there was minimal focus on disease affecting upper extremity.^1–8 Chakraborty et al. described the trends in incidence of Ewing sarcoma of bone in India based on evidence from the national cancer registry programme (1982–2011) and the long bones of the lower limb and upper limb were the most often affected anatomical sites; regarding the individual long bones details were not provided.¹ In the axial skeleton's most often affected bones were the sacrum, coccyx group, and pelvic bone.¹ The probability of Ewing sarcoma in limb bones relative to other bones was 1.6 times higher in the 0–19 age group than in the ≥20 age group.¹

Simpson et al. reviewed a data based on 19 patients who had been treated for Ewing's sarcoma of the upper limb including the shoulder girdle from The Scottish Bone Tumour Registry over the last 40 years.⁸ Shashaa MN et al. published a literature review of fifteen cases on Ewing's sarcoma in scapula and discussed about the epidemiology, clinical manifestation, diagnosis and treatment.¹¹ This explains the rarity of the Ewings sarcoma of upper extremity and difficulty in the management.^12,13

This study's main objective is to close the gaps in the literature on upper extremity Ewing's sarcoma caused by its paucity of publications. In this current publication we assessed the institutional data from 2015 to 2022 and had 26 patients of upper extremity Ewing's sarcoma and had 7 cases of scapula treated with scapulectomy.

Widhe et al. examined 48 cases of Ewing sarcoma and discussed about the clinical characteristics and presenting symptoms of from the patient's initial visit to a doctor.¹⁴ Simpson et al. in 19 patients with upper extremity Ewing evaluated the time from symptoms (pain, swelling) onset to first doctor appointment and found the patient delay varied from 1 to 180 months with a median of 6 months.⁸ Salunke et al. described that in patients with Ewing's sarcoma of foot presented with swelling in 100 % cases and the mean delay in diagnosis for Ewing's sarcoma was 9.5 months (range 6–12 months).¹³ Patients with delay in diagnoses of more than six months and less than six months had disease free survival of 11.5 months and 15 months, respectively.¹³

In Indian subcontinent patients usually present late with an enlarged painful swelling which has been neglected for a while and this can lead to poor prognosis.¹³ In our study we found pain as most common symptom followed by swelling and pathological fracture.Humerus was the most common affected bone followed by scapula in the current study which was similar to published literature.

Chakraborty et al. had 68 % of cases in the 0–19 age group, the age group with the largest proportions was observed to be 10–14 years (25.2 %), followed by 15–19 years (23.3 %) and there was a 1.8:1 male:female ratio.¹ Simpson et al. had 14 of which were in males and 5 of which were in females with a mean age of 19, they were between the ages of 3 and 57.⁸ The mean age of presentation in current study was 17 years,and there was a 1.8:1 male:female ratio.

Sasi et al. had developed a prognostic score using the prognostic factors, which included tumour diameter (5 cm vs. >5 cm), metastasis presence (yes or no), and total leucocyte count (>11000/mm3 vs. 11000/mm3).¹⁵ Each of the two factors, presence of metastases at baseline and tumour diameter >5 cm, received a score of 2, while presence of baseline total leucocyte count >11000/mm3 received a score of 1.¹⁵ Following that, patients were divided into three prognostic risk groups: low risk (score of 0), intermediate risk (score of 1–3), and high risk (score of 4–5).¹⁵ The median survival in the derivation cohort differed significantly between the three groups [estimate not reached in the low-risk group vs. 41.5 months (15.7–67.2 months) in the intermediate risk group vs. 17.2 months (14.7–19.7 months) in the high-risk group].¹⁵

Bacci et al. had assessed the utility of LDH as a tumour marker, the pretreatment serum lactic acid dehydrogenase (LDH) level of 246 patients with Ewing's sarcoma of bone (47 metastatic and 199 localised at presentation).¹⁶ Compared to the patients with localised disease, the metastatic group had a significantly higher percentage of patients (83 % vs. 41 %; p less than 0.01) with elevated serum LDH levels.¹⁶ In the latter group, patients with an elevated serum LDH at admission had a significantly higher rate of relapse following treatment with combined therapy (68.2 % vs. 39.3 %; p less than 0.01) than patients with normal serum levels.¹⁶ In our study, LDH was raised more than twice the normal range which is associated with a poor prognosis³

These findings show that in Ewing's sarcoma of bone, serum LDH levels have a definitive value in establishing prognosis and could also be used to evaluate therapy response. A persistently elevated serum LDH level, or an increasing level following a transient normalisation, is usually followed by relapse.

Our study had an average tumour size of 9–10 cms on magnetic resonance imaging. This can be attributed to delay in diagnosis and referral to a tertiary care centre. Adverse prognostic factors to affect survival include size more than 8 cm, metastasis on presentation, low albumin and elevated LDH.^2–5

Pathological fracture occurs in these patients due to weakening of bones and can led to significant morbidity.^17,18 Bramer et al. in a retrospective study pathological fracture was found in 27 of 289 patients with localised Ewing's sarcoma.¹⁸ Following chemotherapy, 20 patients were treated surgically(15 patients received surgery alone, 5 received surgery and radiotherapy)with 19 receiving limb-saving surgery and one receiving amputation and 7 received radiotherapy alone.¹⁸ Two patients had pathological fracture at presentation in the current study. Pathological fracture affects the local surgical treatment with limb salvage surgery a limb salvage surgery can still be attempted as per response to the neoadjuvant chemotherapy.^17,18

Over the past few decades, Ewing's sarcoma management has evolved to multi-agent chemotherapy in addition to surgery and/or radiation therapy. Long-term survival rates for localised Ewing's sarcoma have significantly improved as a result of multi-disciplinary approach. Chemotherapy response is an important prognostic marker in patients with Ewings sarcoma. In 326 patients with Ewing's sarcoma family tumor (ESFT) treated with adjuvant and neo-adjuvant chemotherapy outcomes were as follows: 287 (88.5 %) remained continuously event free for another 5.5–29 years (mean 11.3 years), while 39 (11.9 %) experienced an unfavourable event after 5 years.¹⁹ Unfavourable events included 25 late relapses (7.7 %), seven radioinduced OSs (2.2 %), three leukaemias, 2 s tumours (both lung cancer), and two severe adriamycin cardiopathies.¹⁹ Adding ifosfamide and etoposide to conventional chemotherapy increased the 5-year event-free period to 70 % and improved overall survival in non-metastatic patients.^7,10,19 Individuals with complete necrosis following chemotherapy are considered to have a favourable response.

Lung metastases were the first late relapse event in 13 patients, followed by bone metastases in three, lung and bone metastases in two, central nervous system metastases in one, and local recurrence in six.¹⁹ The six local recurrences were all followed by bone 3 or lung 3 metastases.¹⁹ Simpson et al. reported a ten-year disease-free survival rate of 100 % for patients with Enneking stage IIA disease and 56 % for patients with stage IIB disease and no survivors of stage III disease.⁸ In the current study the mean tumour necrosis in those who received chemotherapy was 68 % and Four patients had a complete response to chemotherapy.Patients with isolated pulmonary metastases can have a 5 year survival rate of up to 15–20 % with the excision of all lesions¹⁰ Rest patients were referred for palliative radiotherapy for lung or brain metastasis. Disease free survival ranged from 0.5 months to 77 months with a mean period of 23 months.

The surgical treatment of ewings sarcoma with wide margins is a critical step for complete tumour excision, which has a significant impact on patients' oncologic outcomes.^20–23 Surgery was used to treat 136 patients, surgery and radiotherapy for 70, and radiotherapy for 60 patients.²⁰ Despite the fact that patients in all groups were matched for potential risk factors, patients treated with radiotherapy had significantly lower rates of 5-year EFS and local control than patients treated with surgery or surgery and radiotherapy (48 % vs 66 %, p = 0.002; 80 % vs 94 %, p = 0.0001).²⁰ In the current study, limb sparing surgery was performed in 73 % of the cases, while limb amputation was performed in 27 % of the cases, and histopathological studies revealed R0 margins in all patients. Six cases of proximal humerus lesions underwent forequarter amputation. These tumours were either fungating at the time of presentation, following chemotherapy, or had neurovascular bundle encasement making it not feasible to save the limb.

The findings suggest that surgery should always be considered as a local treatment option for Ewings of the extremities. Patients who receive local surgical treatment is far much better than those who receive radiotherapy or surgery plus radiotherapy.^18–20

More investigation is required into the potential risk factors for tumorigenesis associated with age group and anatomical sub-site associations.The study's limitations include its small sample size, retrospective nature and lack of comparison group so we propose future research which includes a multi centre study on this rare disease.

5 Conclusions

This study characterises demographics and oncologic outcomes of upper extremity ewings sarcoma in Indian subpopulation. Pain and swelling are prominent clinical findings at presentation in upper extremity Ewing's sarcoma. Neoadjuvant Chemotherapy and adequate surgical margins can be achieved in these patients with limb saving surgery. The survival rate following limb saving surgery in Ewings sarcoma of upper extremity is comparable to that of patients ampuation surgery and limb saving surgery is a safe option. Ewings sarcoma of upper extremity was associated with higher LDH level which was raised more than twice the normal range and led to worse oncologic outcomes. A comparative study on upper extremity and lower extremity ewings sarcoma will be of help to improve literature on this disease.

Author contribution statement

All authors contributed equally to this study.

Ethical statement

This was a retrospective study and treatment was performed as per standard plan.

Patient/Guardian consent

Obtained.

Funding sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.